Clinical Aspects of Lactose Intolerance in Children and Adults
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H.A. BULLER, E.H.H.M. RINGS, R.K. MONTGOMERY & R.J. GRAND Divisions of Pediatric Gastroenterology and Nutrition, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and The Floating Hospital, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA
Biiller HA, Rings EHHM, Montgomery RK, Grand RJ. Clinical aspects of lactose intolerance in children and adults. Scand J Gastroenterol 1991, 26 Suppl 188, 73-80 The principal carbohydrate of human milk is the disaccharide lactose. In human and all mammalian species, lactose is hydrolyzed in the small intestine by lactase-phlorizin hydrolase, also abbreviated as lactase. The absence of lactase results in the passage of undigested lactose into the large intestine and is associated with a well-known clinical syndrome: lactose intolerance. Low lactase levels result either from intestinal injury or, as in the majority of world’s adult population, from alterations in the genetic expression of lactase. In this review terminology, pathophysiology, symptoms, diagnostic procedures, and therapy of lactose intolerance will be discussed. Key words: Disaccharidase; disaccharide; lactase-phlorizin hydrolase; lactose; lactose intolerance Hans A . Biiller, M. D . , Division of Pediatric Gastroenterology and Nutrition, Dept. of Pediatrics, G8-260, Academic Medical Center, Meibergdreef 9, I105 A Z Amsterdam, The Netherlands
Lactose (milk sugar) is a key nutrient in mammalian milk and contains equimolar quantities of the two monosaccharides, glucose and galactose. Lactose is, from an evolutionary as well as from a biologic viewpoint, a unique sugar because it occurs only in milk as a free molecule. It is synthesized exclusively in the mammary gland during late pregnancy and lactation by lactose synthetase. In normal newborns of all mammalian species, lactose is hydrolyzed in the small intestine by a microvillus membrane disaccharidase, lactase-phlorizin hydrolase, also abbreviated lactase. This intrinsic membrane glycoprotein is solely responsible for the cleavage of lactose into its absorbable monosaccharides. The absence of lactase results in the passage of undigested lactose into the large intestine and is associated with a well-known clinical syndrome. In the colon, lactose is fermented by the colonic flora, resulting in the production of short-chain
fatty acids and hydrogen gas. The gas produced can cause abdominal distention, cramps, nausea, flatus, and pain, and diarrhea may result from the fermentation products and from the osmotic effects of lactose not absorbed in the small intestine. The severity of symptoms varies depending on the amount of lactose that each individual can tolerate. A most intriguing aspect of lactase is the developmental pattern of its specific activity found in virtually all mammals studied. In all animals and most humans a similar motif occurs: the specific activity of lactase increases during the last trimester of gestation, shows maximal activity in the newborn period, and then begins to decline, reaching low levels in adulthood, whereas in a minority of the human population the specific activity remains high throughout life. In contrast, the specific activities of the other intestinal disaccharidases, sucrase-isomaltase and maltase-
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glucoamylase (1, 2 ) are low during the suckling period and gradually increase around the time of weaning to reach high adult levels. TERMINOLOGY
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To avoid confusion of certain terminologies, it is appropriate to review some basic definitions. Milk intolerance. The appearance of gastrointestinal symptoms such as nausea, cramps, abdominal distention, pain, flatulence, and diarrhea after the consumption of milk defines milk intolerance. These symptoms can be based on the inability to digest lactose but also may reflect a sensitivity to milk proteins. Allergy to milk proteins often involves symptoms of the skin and the respiratory tract on the basis of an immunologic process. Thus, milk intolerance is often the term used by patients to describe their complaints. Lactose intolerance. The term lactose intolerance is used when similar gastrointestinal symptoms as described above are experienced after ingestion of lactose. Lactose malabsorption. This term is reserved for those patients in whom the intestinal (ma1)absorption of lactose has been investigated using an appropriate lactose absorption (or tolerance) test (such as breath hydrogen test or lactose tolerance test). Interestingly, lactose malabsorption is not necessarily accompanied by the clinical diagnosis of lactose intolerance. Lactase deficiency. Only when a low or, very rarely, no level of lactase activity has been determined in a small-intestinal biopsy sample is it correct to use the term lactase deficiency. Lactase deficiency is either a primary or a secondary event. Primary lactase deficiency occurs as a developmental process in premature infants or as a rare clinical syndrome (3,4). It also appears as ‘late-onset lactase deficiency’ in most of the world’s population after the age of 5 years. Secondary lactase deficiency is found after mucosal injury (3). The developmental form of primary lactase deficiency is seen in premature babies born before 36 weeks of gestation (3). The congenital form is
very rare (4) and is characterized by the total absence or sometimes very low levels of the enzyme, most likely the result of an autosomal recessive inheritance (4). This disorder was potentially lethal until lactose-free milk became available. There is a concentration of congenital lactase deficiency in Finland. Late-onset lactase deficiency is the term commonly used for the genetically determined decline of lactase enzyme levels during weaning and the maintenance of these low levels in adulthood (approximately 10% of the values at birth) (5). Available data indicate that persistence of high levels of lactase enzyme beyond infancy is probably an autosomal dominant trait. Populations that express this genetic phenotype are considered to be ‘lactase-sufficient’. The concept of lateonset lactase deficiency is based on the acceptance of this persistence of lactase activity as ‘normal’, whereas the fall in lactase-specific activity has been considered ‘abnormal’. However, this interpretation demands re-evaluation, as it is now clear that persistence of the capacity for lactose digestion in humans evolved relatively recently. It has been estimated that the presence of high lactase activity in adulthood emerged over a span estimated to be a minimum of 10,000 years and that it occurred simultaneously in at least three loci around the world (6). In contrast, most of the world’s population, and virtually all placental mammals studied, show a reduction of lactase activity in adulthood. Thus, it would be better to indicate the level of lactase enzyme activity rather than to use the term ‘deficiency’, which wrongly implies the existence of a disease. Secondary lactase deficiency occurs when the intestinal mucosa is damaged by acute or chronic infection, drugs, or other toxic agents. These also affect the other disaccharidases, but lactase seems to be much more vulnerable, and return of enzyme activity lags behind the return of normal mucosal morphology (7-9). Diseases that can cause villus flattening or damage to the epithelium include infectious gastroenteritis (rotavirus is the commonest cause), severe parasitic infections (giardiasis), gluten-sensitive enteropathy (celiac disease), tropical sprue, radiation enteritis, druginduced enteritis (colchicine) or cytostatica, and
Clinical Aspects of Lactose Intolerance
Crohn’s disease involving the small intestine (3, 5, 10).
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PATHOPHYSIOLOGY O F LACTOSE INTOLERANCE Lactose concentration in milk is inversely related to the content of fat and protein (11); human milk contains the highest concentration (7%) of lactose. In breast-fed infants and in most bottle-fed infants, until the introduction of cereals and fruits (from the age of 4 months), lactose comprises the total carbohydrate source. Lactase activity, expressed either as units of activity per milligram protein or per gram mucosal weight is considerably lower than for the other disaccharidases (12). The location of the enzyme on the villus-crypt axis (with maximal expression at the upper villus) makes it particularly sensitive to villus injury (13). All infants, however, except those with congenital lactase deficiency, are able to digest lactose regardless of their ethnic origins. MacLean et al. (14) showed that in preterm infants 66% of ingested lactose reaches the colon, where it is fermented by bacteria (15). In term infants lactose hydrolysis is almost complete, but colonic salvage still occurs (3, 16, 17). However, in the several-months-old healthy infant, the amount of ingested lactose is almost completely hydrolyzed in the small intestine, and virtually no lactose reaches the colon. The severity of lactose malabsorption and the extent of symptoms are not only a function of the amount of lactase in the small intestine, but also of several other factors. First, the amount of ingested lactose is important. When lactose is consumed in quantities exceeding the capacity of available lactase, malabsorption symptoms may occur. In this case, lactase activity found in a biopsy specimen may be normal or abnormal. The second factor concerns gastric emptying time. A slow gastric emptying increases the absorption of lactose (18, 19). A third factor is the intestinal transit time of lactose. Ladas et al. (20) showed that the transit time decreased in parallel with the severity of the lactose intolerance symptoms. The fourth factor is the colonic flora, which provides compensatory mechanisms influencing the sever-
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ity of symptoms. Fermentation by bacterial flora in the colon (mostly anaerobes) of unhydrolyzed lactose leads to the formation of short-chain fatty acids (butyrate, proprionate, lactate, and acetate) and gasses in the form of HZ,C 0 2 , and CH4. The extent of utilization of these products by the colon will affect the symptoms of malabsorption (18,21, 22). The quantity of colonic bacteria, the organisms involved, and the absorption of fermentation products differ considerably among individuals, affecting the degree of complaints. The fifth factor is the difference in symptoms found when lactose is ingested in the form of milk compared with those observed when lactose is administered in water (18, 23). This difference is presumably due to slower emptying rates of the stomach for milk. The presence of lactose in the lumen of the small intestine, not hydrolyzed by lactase, provides an osmotic force for water to move into the intestine, resulting in an increase of volume. This stimulates peristalsis of the small intestine, leading to increased rate of transit and further impairing absorption. The voluminous content of the intestine gives rise to the borborygmi, bloating, pain, and cramps. Fermentation of carbohydrate in the colon leads to lowering of the pH, which stimulates colonic peristalsis, augmenting the diarrhea (18). In contrast, the short-chain fatty acids stimulate absorption of salt and water (24). Gas formation leads to flatulence and cramps. CLINICAL SYMPTOMS The clinical symptoms of lactose malabsorption may be either acute or chronic. Typical acute complaints include nausea, abdominal pain, cramps or distention, flatulence, and diarrhea; in children and adolescents, vomiting may predominate. The feeling of abdominal fullness and sometimes nausea are usually experienced within 30 min of ingestion of the test dose of lactose, whereas the abdominal pain, flatulence, and, less frequently, diarrhea occur within 1-2 h after consumption of lactose. It is important to note that the severity of the symptoms is variable among lactose malabsorbers and that merely recording of symptoms of intolerance after a lactose load is an
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unreliable method of diagnosing lactose malabsorption ( 5 ) . In areas with low lactase levels in the adult population clinically important manifestations of lactose intolerance are rare, most likely due to the self-imposed restriction of milk or milk product ingestion. Even in areas with high milk consumption and generally low lactase levels, no major health problems are observed as a result of lactose intolerance ( 5 ) . The most important aspects of lactose intolerance, its symptoms and chronic effects, are encountered in young children, when low levels of lactase enzyme are the result of mucosal damage, as, for example, found after gastrointestinal infection. This is probably one of the major factors contributing to the malnutrition problem in the Third World. The acute symptoms of the infection itself (for example, rotavirus causing diarrhea and loss of nutrients) may lead to dehydration and electrolyte imbalances. Preexisting malnutrition (often as a consequence of previous intestinal infections) impairs mucosal function and recovery (25). The association of lactose malabsorption and/or deficiency with irritable bowel syndrome or recurrent abdominal pain has received considerable attention in the literature. The true relationship, however, between these diseases and lactose intolerance remains largely undefined (27, 28).
DIAGNOSIS The diagnosis of lactose malabsorption and its pathogenesis are based on a combination of clinical findings (lactose intolerance) (26) and the results of appropriate tests (29-33). Several tests are available. Fecal analysis. In general, the presence of low fecal pH and reducing substances indicates lactose malabsorption but is only valid when lactose has been ingested, intestinal transit time is rapid, stools are collected fresh and assayed immediately, and when bacterial metabolism of colonic carbohydrate is incomplete (30). Confirmation of lactose malabsorption is best accomplished using more specific tests. Lactose absorption test. The capacity for lactose absorution can be measured usine the lactose Y
absorption test, previously known as the lactose tolerance test (31). The standard test is performed after an overnight fast. Fasting glucose levels taken before the lactose test load are used as zero time values. After lactose ingestion (usually 2 g/kg, with a maximum of 50 g water), capillary blood samples are obtained to measure the blood glucose levels. A rise of less than 1.2mmolA or 20 mg% is considered a ‘flat curve’ and an indication of malabsorption (34). In adults the test has a sensitivity and specificity of 76% and 96%, respectively. In children it is cumbersome, invasive, and time-cconsuming and has largely been replaced by the lactose breath hydrogen test (10). It has been shown by several investigators that the lactose absorption test has a poor correlation with mucosal lactase levels (35, 36). Breath hydrogen test. Although this test really measures lactose non-absorption rather than lactose hydrolysis and monosaccharide uptake, its sensitivity and specificity are superior to those for the lactose absorption test, and it is simple and non-invasive (33,37,38). Factors that increase the value of the test are 1) knowledge of the capacity of the subject to produce hydrogen (lactulose test), 2) duration and frequency of sampling, 3) the use of lower base-line values (10 ppm), and 4) the presentation of the test dose as a 20% solution in water. The production of hydrogen, which is excreted in the breath, is the result of fermentation of undigested lactose by colonic bacteria. The concentration of hydrogen in the breath samples is determined by gas chromatography. It is safe to state that more than 20 ppm is a strong indication of malabsorption, whereas a rise between 10 and 20 ppm is likely to be indicative of malabsorption only when accompanied by symptoms (39, 40). Many investigators have reviewed various aspects of the lactose breath hydrogen test (27-29, 31, 32). It is considered to be the most accurate and least invasive method for demonstrating the malabsorption of lactose after a test load (41,42). The only critical aspect is the capability of the patient’s colonic bacteria to produce hydrogen from lactose (estimates are that 2-20% of patients are colonized with bacteria incapable of producing hydrogen (43)). The hydrolysis of lactose in the small bowel is incomplete in newborns up to the age - of 4
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Clinical Aspects of Lactose Intolerance
months (17, 44,454, indicating the validity of the test beyond this age. Other breath tests using radioactively labeled carbon have been described (5, 33) but are expensive, less reliable, and inappropriate for use in children (43). Intestinal biopsy. The assay of lactase activity in small-bowel biopsy samples establishes the presence of lactase deficiency in populations with lateonset lactase deficiency (46-48). However, when lactase deficiency accompanies intestinal injury, the lesion may be focal or patchy; consequently, intestinal biopsy samples may not yield an abnormal result even when histology is abnormal (49). Furthermore, this test is invasive, requires some (although not excessive) radiation exposure in most pediatric cases, and is time-consuming. Lactase activity is determined by biochemical methods (47) in a peroral small-intestinal specimen, usually obtained several centimeters beyond the ligament of Treitz. This location is preferred because lactase activity is known to be lower in the duodenum, higher in the jejunum, and low in the ileum (36). Studies are available which have compared intestinal histology, lactase activity, and breath hydrogen test results (27, 28, 43, 49). In adult healthy subjects with normal histology, smallintestinal lactase activity correlated closely with the results of the lactose breath hydrogen test. However, in patients with chronic diarrhea, different findings were obtained. Of those with abnormal intestinal histology, approximately 75% had abnormal lactose breath hydrogen values (sensitivity, 75%); however, in patients with normal histology the lactose breath hydrogen test was only 54% specific. Very similar values were found when lactase activities on biopsy were compared with results of lactose breath hydrogen tests (39,49). The explanation for these seemingly discrepant results must be the presence of a patchy villus lesion in those with ‘normal’ histology, leading to the absence of positive biopsy findings in the specimen examined. Accordingly, an abnormal lactose breath hydrogen test is of value in identifying those patients who will be symptomatic after lactose ingestion. A normal lactose breath hydrogen test does not rule out an intestinal mucosal abnormality and should not be
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used to avoid an intestinal biopsy in the diagnosis of suspected mucosal disease (such as glutensensitive enteropathy) (49). TREATMENT In the treatment of lactose malabsorption it is important to know the lactose content of various milk products. Lactose generally represents up to 30% of the caloric intake when milk is consumed in normal quantities by infants and young children. Human milk contains approximately 7% (g/lOOg) lactose, while in cow milk, chocolate milk, buttermilk, low-fat milk this percentage is around 4.8% (50). Condensed, dried (unreconstituted) and evaporated milks contain very high percentages of lactose; 14%, So%, and 11%, respectively. The lactose content of ice cream, light cream, yoghurt, ricotta, and cottage cheese is considerable, on average 3.8%. Other milk products, butter, and cheese (blue, Muenster, Edam, Gouda, Camembert, mozarella, cheddar) are low in lactose, around 1% or less (50). If treatment of lactose intolerance is required, four general principles are customarily observed: 1) reduction or restriction of dietary lactose, 2) substitution of alternative nutrient sources to avoid reduction in energy intake, 3) regulation of calcium intake, and 4) use of a commercially available enzyme substitute. Milk reduction or restriction When lactose restriction is necessary, the patient must be instructed to read labels of commercially prepared foods, as hidden lactose, not only in the form of lactose or milk but also as whey, curds, caseinate, and lactoglobulin may be difficult to identify. Lactose is added to increase bulk and texture as well as flavor to many food products (bread and other baked goods, cereals, soups, margarine, lunch meats, salad dressing, candies, and mixes for pancakes and cookies) (50). Low-lactose or lactose-free milk formulas are available for infant feeding. Substitution Live-culture yoghurt, which contains endogenous beta-galactosidase, is a useful alternative
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source of both calcium and calories and may be well tolerated by some lactose-intolerant patients (51). Many cheeses contain little lactose and can be freely consumed by most patients. The use of unfermented acidophilus milk showed no effect in relieving the symptoms in patients with ‘irritable bowel syndrome’, nor did it show any beneficial effects in lactase-deficient patients (52). Dietary constituents lacking lactose must be recommended when lactose is restricted or eliminated from the diet, and appropriate counseling is needed to ensure that the patient will ingest adequate quantities of nutrients, at least at the RDA for age (53).
Calcium Calcium is found in many vegetables (broccoli, collard greens), fish (oysters, salmon, sardines, shrimp), nuts, and tofu. Calcium supplementation in the form of calcium carbonate or citrate are popular and effective; in infants, liquid calcium gluconate is readily tolerated and available (53). Enzyme substitution Commercially available ‘lactase’ preparations are actually bacterial or yeast beta-galactosidases. When added to lactose-containing food or ingested with meals containing lactose, these are effective in reducing symptoms and breath hydrogen values in many lactose-intolerant subjects (54, 55). However, they are not capable of completely hydrolyzing all dietary lactose, and the results of their use in patients is variable. The efficiency of these lactase substitutes may be influenced by the inhibition of the enzyme by galactose during in vitro hydrolysis of lactose (56). This may explain in part the variability of success of pretreatment of milk by these beta-galactosidases and has stimulated the use of products that provide in vivo hydrolysis. Rosada et al. (57) found, in adult lactose malabsorbers, that adding yeast lactase just before consumption caused a reduction of 62% in breath hydrogen excretion and significantly eliminated symptoms of intolerance. Barillas (58) showed that adding yeast lactase just before ingestion of 240ml of milk produced an 82% relative reduction in hydrogen excretion
when compared with 240ml of milk alone in healthy Guatemalan preschool children.
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H.A. BULLER, E.H.H.M. RINGS, R.K. MONTGOMERY & R.J. GRAND Divisions of Pediatric Gastroenterology and Nutrition, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and The Floating Hospital, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA
Biiller HA, Rings EHHM, Montgomery RK, Grand RJ. Clinical aspects of lactose intolerance in children and adults. Scand J Gastroenterol 1991, 26 Suppl 188, 73-80 The principal carbohydrate of human milk is the disaccharide lactose. In human and all mammalian species, lactose is hydrolyzed in the small intestine by lactase-phlorizin hydrolase, also abbreviated as lactase. The absence of lactase results in the passage of undigested lactose into the large intestine and is associated with a well-known clinical syndrome: lactose intolerance. Low lactase levels result either from intestinal injury or, as in the majority of world’s adult population, from alterations in the genetic expression of lactase. In this review terminology, pathophysiology, symptoms, diagnostic procedures, and therapy of lactose intolerance will be discussed. Key words: Disaccharidase; disaccharide; lactase-phlorizin hydrolase; lactose; lactose intolerance Hans A . Biiller, M. D . , Division of Pediatric Gastroenterology and Nutrition, Dept. of Pediatrics, G8-260, Academic Medical Center, Meibergdreef 9, I105 A Z Amsterdam, The Netherlands
Lactose (milk sugar) is a key nutrient in mammalian milk and contains equimolar quantities of the two monosaccharides, glucose and galactose. Lactose is, from an evolutionary as well as from a biologic viewpoint, a unique sugar because it occurs only in milk as a free molecule. It is synthesized exclusively in the mammary gland during late pregnancy and lactation by lactose synthetase. In normal newborns of all mammalian species, lactose is hydrolyzed in the small intestine by a microvillus membrane disaccharidase, lactase-phlorizin hydrolase, also abbreviated lactase. This intrinsic membrane glycoprotein is solely responsible for the cleavage of lactose into its absorbable monosaccharides. The absence of lactase results in the passage of undigested lactose into the large intestine and is associated with a well-known clinical syndrome. In the colon, lactose is fermented by the colonic flora, resulting in the production of short-chain
fatty acids and hydrogen gas. The gas produced can cause abdominal distention, cramps, nausea, flatus, and pain, and diarrhea may result from the fermentation products and from the osmotic effects of lactose not absorbed in the small intestine. The severity of symptoms varies depending on the amount of lactose that each individual can tolerate. A most intriguing aspect of lactase is the developmental pattern of its specific activity found in virtually all mammals studied. In all animals and most humans a similar motif occurs: the specific activity of lactase increases during the last trimester of gestation, shows maximal activity in the newborn period, and then begins to decline, reaching low levels in adulthood, whereas in a minority of the human population the specific activity remains high throughout life. In contrast, the specific activities of the other intestinal disaccharidases, sucrase-isomaltase and maltase-
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glucoamylase (1, 2 ) are low during the suckling period and gradually increase around the time of weaning to reach high adult levels. TERMINOLOGY
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To avoid confusion of certain terminologies, it is appropriate to review some basic definitions. Milk intolerance. The appearance of gastrointestinal symptoms such as nausea, cramps, abdominal distention, pain, flatulence, and diarrhea after the consumption of milk defines milk intolerance. These symptoms can be based on the inability to digest lactose but also may reflect a sensitivity to milk proteins. Allergy to milk proteins often involves symptoms of the skin and the respiratory tract on the basis of an immunologic process. Thus, milk intolerance is often the term used by patients to describe their complaints. Lactose intolerance. The term lactose intolerance is used when similar gastrointestinal symptoms as described above are experienced after ingestion of lactose. Lactose malabsorption. This term is reserved for those patients in whom the intestinal (ma1)absorption of lactose has been investigated using an appropriate lactose absorption (or tolerance) test (such as breath hydrogen test or lactose tolerance test). Interestingly, lactose malabsorption is not necessarily accompanied by the clinical diagnosis of lactose intolerance. Lactase deficiency. Only when a low or, very rarely, no level of lactase activity has been determined in a small-intestinal biopsy sample is it correct to use the term lactase deficiency. Lactase deficiency is either a primary or a secondary event. Primary lactase deficiency occurs as a developmental process in premature infants or as a rare clinical syndrome (3,4). It also appears as ‘late-onset lactase deficiency’ in most of the world’s population after the age of 5 years. Secondary lactase deficiency is found after mucosal injury (3). The developmental form of primary lactase deficiency is seen in premature babies born before 36 weeks of gestation (3). The congenital form is
very rare (4) and is characterized by the total absence or sometimes very low levels of the enzyme, most likely the result of an autosomal recessive inheritance (4). This disorder was potentially lethal until lactose-free milk became available. There is a concentration of congenital lactase deficiency in Finland. Late-onset lactase deficiency is the term commonly used for the genetically determined decline of lactase enzyme levels during weaning and the maintenance of these low levels in adulthood (approximately 10% of the values at birth) (5). Available data indicate that persistence of high levels of lactase enzyme beyond infancy is probably an autosomal dominant trait. Populations that express this genetic phenotype are considered to be ‘lactase-sufficient’. The concept of lateonset lactase deficiency is based on the acceptance of this persistence of lactase activity as ‘normal’, whereas the fall in lactase-specific activity has been considered ‘abnormal’. However, this interpretation demands re-evaluation, as it is now clear that persistence of the capacity for lactose digestion in humans evolved relatively recently. It has been estimated that the presence of high lactase activity in adulthood emerged over a span estimated to be a minimum of 10,000 years and that it occurred simultaneously in at least three loci around the world (6). In contrast, most of the world’s population, and virtually all placental mammals studied, show a reduction of lactase activity in adulthood. Thus, it would be better to indicate the level of lactase enzyme activity rather than to use the term ‘deficiency’, which wrongly implies the existence of a disease. Secondary lactase deficiency occurs when the intestinal mucosa is damaged by acute or chronic infection, drugs, or other toxic agents. These also affect the other disaccharidases, but lactase seems to be much more vulnerable, and return of enzyme activity lags behind the return of normal mucosal morphology (7-9). Diseases that can cause villus flattening or damage to the epithelium include infectious gastroenteritis (rotavirus is the commonest cause), severe parasitic infections (giardiasis), gluten-sensitive enteropathy (celiac disease), tropical sprue, radiation enteritis, druginduced enteritis (colchicine) or cytostatica, and
Clinical Aspects of Lactose Intolerance
Crohn’s disease involving the small intestine (3, 5, 10).
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PATHOPHYSIOLOGY O F LACTOSE INTOLERANCE Lactose concentration in milk is inversely related to the content of fat and protein (11); human milk contains the highest concentration (7%) of lactose. In breast-fed infants and in most bottle-fed infants, until the introduction of cereals and fruits (from the age of 4 months), lactose comprises the total carbohydrate source. Lactase activity, expressed either as units of activity per milligram protein or per gram mucosal weight is considerably lower than for the other disaccharidases (12). The location of the enzyme on the villus-crypt axis (with maximal expression at the upper villus) makes it particularly sensitive to villus injury (13). All infants, however, except those with congenital lactase deficiency, are able to digest lactose regardless of their ethnic origins. MacLean et al. (14) showed that in preterm infants 66% of ingested lactose reaches the colon, where it is fermented by bacteria (15). In term infants lactose hydrolysis is almost complete, but colonic salvage still occurs (3, 16, 17). However, in the several-months-old healthy infant, the amount of ingested lactose is almost completely hydrolyzed in the small intestine, and virtually no lactose reaches the colon. The severity of lactose malabsorption and the extent of symptoms are not only a function of the amount of lactase in the small intestine, but also of several other factors. First, the amount of ingested lactose is important. When lactose is consumed in quantities exceeding the capacity of available lactase, malabsorption symptoms may occur. In this case, lactase activity found in a biopsy specimen may be normal or abnormal. The second factor concerns gastric emptying time. A slow gastric emptying increases the absorption of lactose (18, 19). A third factor is the intestinal transit time of lactose. Ladas et al. (20) showed that the transit time decreased in parallel with the severity of the lactose intolerance symptoms. The fourth factor is the colonic flora, which provides compensatory mechanisms influencing the sever-
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ity of symptoms. Fermentation by bacterial flora in the colon (mostly anaerobes) of unhydrolyzed lactose leads to the formation of short-chain fatty acids (butyrate, proprionate, lactate, and acetate) and gasses in the form of HZ,C 0 2 , and CH4. The extent of utilization of these products by the colon will affect the symptoms of malabsorption (18,21, 22). The quantity of colonic bacteria, the organisms involved, and the absorption of fermentation products differ considerably among individuals, affecting the degree of complaints. The fifth factor is the difference in symptoms found when lactose is ingested in the form of milk compared with those observed when lactose is administered in water (18, 23). This difference is presumably due to slower emptying rates of the stomach for milk. The presence of lactose in the lumen of the small intestine, not hydrolyzed by lactase, provides an osmotic force for water to move into the intestine, resulting in an increase of volume. This stimulates peristalsis of the small intestine, leading to increased rate of transit and further impairing absorption. The voluminous content of the intestine gives rise to the borborygmi, bloating, pain, and cramps. Fermentation of carbohydrate in the colon leads to lowering of the pH, which stimulates colonic peristalsis, augmenting the diarrhea (18). In contrast, the short-chain fatty acids stimulate absorption of salt and water (24). Gas formation leads to flatulence and cramps. CLINICAL SYMPTOMS The clinical symptoms of lactose malabsorption may be either acute or chronic. Typical acute complaints include nausea, abdominal pain, cramps or distention, flatulence, and diarrhea; in children and adolescents, vomiting may predominate. The feeling of abdominal fullness and sometimes nausea are usually experienced within 30 min of ingestion of the test dose of lactose, whereas the abdominal pain, flatulence, and, less frequently, diarrhea occur within 1-2 h after consumption of lactose. It is important to note that the severity of the symptoms is variable among lactose malabsorbers and that merely recording of symptoms of intolerance after a lactose load is an
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unreliable method of diagnosing lactose malabsorption ( 5 ) . In areas with low lactase levels in the adult population clinically important manifestations of lactose intolerance are rare, most likely due to the self-imposed restriction of milk or milk product ingestion. Even in areas with high milk consumption and generally low lactase levels, no major health problems are observed as a result of lactose intolerance ( 5 ) . The most important aspects of lactose intolerance, its symptoms and chronic effects, are encountered in young children, when low levels of lactase enzyme are the result of mucosal damage, as, for example, found after gastrointestinal infection. This is probably one of the major factors contributing to the malnutrition problem in the Third World. The acute symptoms of the infection itself (for example, rotavirus causing diarrhea and loss of nutrients) may lead to dehydration and electrolyte imbalances. Preexisting malnutrition (often as a consequence of previous intestinal infections) impairs mucosal function and recovery (25). The association of lactose malabsorption and/or deficiency with irritable bowel syndrome or recurrent abdominal pain has received considerable attention in the literature. The true relationship, however, between these diseases and lactose intolerance remains largely undefined (27, 28).
DIAGNOSIS The diagnosis of lactose malabsorption and its pathogenesis are based on a combination of clinical findings (lactose intolerance) (26) and the results of appropriate tests (29-33). Several tests are available. Fecal analysis. In general, the presence of low fecal pH and reducing substances indicates lactose malabsorption but is only valid when lactose has been ingested, intestinal transit time is rapid, stools are collected fresh and assayed immediately, and when bacterial metabolism of colonic carbohydrate is incomplete (30). Confirmation of lactose malabsorption is best accomplished using more specific tests. Lactose absorption test. The capacity for lactose absorution can be measured usine the lactose Y
absorption test, previously known as the lactose tolerance test (31). The standard test is performed after an overnight fast. Fasting glucose levels taken before the lactose test load are used as zero time values. After lactose ingestion (usually 2 g/kg, with a maximum of 50 g water), capillary blood samples are obtained to measure the blood glucose levels. A rise of less than 1.2mmolA or 20 mg% is considered a ‘flat curve’ and an indication of malabsorption (34). In adults the test has a sensitivity and specificity of 76% and 96%, respectively. In children it is cumbersome, invasive, and time-cconsuming and has largely been replaced by the lactose breath hydrogen test (10). It has been shown by several investigators that the lactose absorption test has a poor correlation with mucosal lactase levels (35, 36). Breath hydrogen test. Although this test really measures lactose non-absorption rather than lactose hydrolysis and monosaccharide uptake, its sensitivity and specificity are superior to those for the lactose absorption test, and it is simple and non-invasive (33,37,38). Factors that increase the value of the test are 1) knowledge of the capacity of the subject to produce hydrogen (lactulose test), 2) duration and frequency of sampling, 3) the use of lower base-line values (10 ppm), and 4) the presentation of the test dose as a 20% solution in water. The production of hydrogen, which is excreted in the breath, is the result of fermentation of undigested lactose by colonic bacteria. The concentration of hydrogen in the breath samples is determined by gas chromatography. It is safe to state that more than 20 ppm is a strong indication of malabsorption, whereas a rise between 10 and 20 ppm is likely to be indicative of malabsorption only when accompanied by symptoms (39, 40). Many investigators have reviewed various aspects of the lactose breath hydrogen test (27-29, 31, 32). It is considered to be the most accurate and least invasive method for demonstrating the malabsorption of lactose after a test load (41,42). The only critical aspect is the capability of the patient’s colonic bacteria to produce hydrogen from lactose (estimates are that 2-20% of patients are colonized with bacteria incapable of producing hydrogen (43)). The hydrolysis of lactose in the small bowel is incomplete in newborns up to the age - of 4
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months (17, 44,454, indicating the validity of the test beyond this age. Other breath tests using radioactively labeled carbon have been described (5, 33) but are expensive, less reliable, and inappropriate for use in children (43). Intestinal biopsy. The assay of lactase activity in small-bowel biopsy samples establishes the presence of lactase deficiency in populations with lateonset lactase deficiency (46-48). However, when lactase deficiency accompanies intestinal injury, the lesion may be focal or patchy; consequently, intestinal biopsy samples may not yield an abnormal result even when histology is abnormal (49). Furthermore, this test is invasive, requires some (although not excessive) radiation exposure in most pediatric cases, and is time-consuming. Lactase activity is determined by biochemical methods (47) in a peroral small-intestinal specimen, usually obtained several centimeters beyond the ligament of Treitz. This location is preferred because lactase activity is known to be lower in the duodenum, higher in the jejunum, and low in the ileum (36). Studies are available which have compared intestinal histology, lactase activity, and breath hydrogen test results (27, 28, 43, 49). In adult healthy subjects with normal histology, smallintestinal lactase activity correlated closely with the results of the lactose breath hydrogen test. However, in patients with chronic diarrhea, different findings were obtained. Of those with abnormal intestinal histology, approximately 75% had abnormal lactose breath hydrogen values (sensitivity, 75%); however, in patients with normal histology the lactose breath hydrogen test was only 54% specific. Very similar values were found when lactase activities on biopsy were compared with results of lactose breath hydrogen tests (39,49). The explanation for these seemingly discrepant results must be the presence of a patchy villus lesion in those with ‘normal’ histology, leading to the absence of positive biopsy findings in the specimen examined. Accordingly, an abnormal lactose breath hydrogen test is of value in identifying those patients who will be symptomatic after lactose ingestion. A normal lactose breath hydrogen test does not rule out an intestinal mucosal abnormality and should not be
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used to avoid an intestinal biopsy in the diagnosis of suspected mucosal disease (such as glutensensitive enteropathy) (49). TREATMENT In the treatment of lactose malabsorption it is important to know the lactose content of various milk products. Lactose generally represents up to 30% of the caloric intake when milk is consumed in normal quantities by infants and young children. Human milk contains approximately 7% (g/lOOg) lactose, while in cow milk, chocolate milk, buttermilk, low-fat milk this percentage is around 4.8% (50). Condensed, dried (unreconstituted) and evaporated milks contain very high percentages of lactose; 14%, So%, and 11%, respectively. The lactose content of ice cream, light cream, yoghurt, ricotta, and cottage cheese is considerable, on average 3.8%. Other milk products, butter, and cheese (blue, Muenster, Edam, Gouda, Camembert, mozarella, cheddar) are low in lactose, around 1% or less (50). If treatment of lactose intolerance is required, four general principles are customarily observed: 1) reduction or restriction of dietary lactose, 2) substitution of alternative nutrient sources to avoid reduction in energy intake, 3) regulation of calcium intake, and 4) use of a commercially available enzyme substitute. Milk reduction or restriction When lactose restriction is necessary, the patient must be instructed to read labels of commercially prepared foods, as hidden lactose, not only in the form of lactose or milk but also as whey, curds, caseinate, and lactoglobulin may be difficult to identify. Lactose is added to increase bulk and texture as well as flavor to many food products (bread and other baked goods, cereals, soups, margarine, lunch meats, salad dressing, candies, and mixes for pancakes and cookies) (50). Low-lactose or lactose-free milk formulas are available for infant feeding. Substitution Live-culture yoghurt, which contains endogenous beta-galactosidase, is a useful alternative
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source of both calcium and calories and may be well tolerated by some lactose-intolerant patients (51). Many cheeses contain little lactose and can be freely consumed by most patients. The use of unfermented acidophilus milk showed no effect in relieving the symptoms in patients with ‘irritable bowel syndrome’, nor did it show any beneficial effects in lactase-deficient patients (52). Dietary constituents lacking lactose must be recommended when lactose is restricted or eliminated from the diet, and appropriate counseling is needed to ensure that the patient will ingest adequate quantities of nutrients, at least at the RDA for age (53).
Calcium Calcium is found in many vegetables (broccoli, collard greens), fish (oysters, salmon, sardines, shrimp), nuts, and tofu. Calcium supplementation in the form of calcium carbonate or citrate are popular and effective; in infants, liquid calcium gluconate is readily tolerated and available (53). Enzyme substitution Commercially available ‘lactase’ preparations are actually bacterial or yeast beta-galactosidases. When added to lactose-containing food or ingested with meals containing lactose, these are effective in reducing symptoms and breath hydrogen values in many lactose-intolerant subjects (54, 55). However, they are not capable of completely hydrolyzing all dietary lactose, and the results of their use in patients is variable. The efficiency of these lactase substitutes may be influenced by the inhibition of the enzyme by galactose during in vitro hydrolysis of lactose (56). This may explain in part the variability of success of pretreatment of milk by these beta-galactosidases and has stimulated the use of products that provide in vivo hydrolysis. Rosada et al. (57) found, in adult lactose malabsorbers, that adding yeast lactase just before consumption caused a reduction of 62% in breath hydrogen excretion and significantly eliminated symptoms of intolerance. Barillas (58) showed that adding yeast lactase just before ingestion of 240ml of milk produced an 82% relative reduction in hydrogen excretion
when compared with 240ml of milk alone in healthy Guatemalan preschool children.
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56. Rand AG. Enzyme technology and the development of lactose-hydrolyzed milk. In: Paige DM, Bayless TM, eds. Lactose digestion: clinical and nutritional implications. John Hopkins University Press, Baltimore, 1981, 21%230 57. Rosada JL, Solomons NW, Lisker R, Bourges H. Enzyme replacement therapy for primary adult lactase deficiency. Gastroenterology 1984, 87, 1072-1082 58. Barillas C, Solomons NW. Effective reduction of lactose maldigestion in preschool children by direct addition of beta-galactosidases to milk at mealtime. Pediatrics 1987, 79, 766-772
